p53 inhibitors and therapeutic use of the same

Abstract

The therapeutic use of temporary p53 inhibitors in the treatment of p53-mediated diseases, conditions, and injuries is disclosed.

What is claimed is:  
     
       1. A method of treating an individual suffering from a p53-deficient cancerous tumor sensitive to treatment with a temporary p53 inhibitor comprising administering a therapeutically effective amount of a temporary p53 inhibitor to the individual, said temporary p53 inhibitor having a structural formula:                    
       wherein X is S, 
       m is 0 or 1,  
       n is 1 to 4,  
       R 1  and R 2  are taken together to form an aliphatic or aromatic carbocyclic 5- to 8-membered ring, and  
       R 3  is selected from the group consisting of phenyl, 4-chlorophenyl, 4-nitrophenyl, 3-nitrophenyl, 4-methylphenyl, 4-phenylphenyl, and 4-bromophenyl;  
       or pharmaceutically acceptable salts or hydrates thereof.  
     
     
       2. The method of  claim 1  wherein X is S; m and n each are 1; and R 1  and R 2  are taken together to form a 5- or 6-membered aliphatic carbocyclic ring. 
     
     
       3. The method of  claim 1  wherein the p53 inhibitor has the structure                    
       wherein R 9  is hydro, chloro, nitro, methyl, phenyl, or bromo. 
     
     
       4. The method of  claim 1  wherein the p53 inhibitor comprises 2-[2-imino-4,5,6,7-tetrahydro-1,3-benzothiazol-3(2H)-yl]-1-(4-methylphenyl)-1-ethanone; 
       2-[2-imino-4,5,6,7-tetrahydro-1,3-benzothiazol-3(2H)-yl]-1-(biphenyl)-1-ethanone; or a mixture thereof,  
       and pharmaceutically acceptable salts and hydrates thereof. 
     
     
       5. A method of reducing or eliminating normal cell death attributable to contraction of a cancer comprising administering a therapeutically effective amount of a temporary p53 inhibitor to a mammal suffering from the cancer to reversibly inhibit p53 activity in a cell sensitive to the temporary p53 inhibitor, 
       said temporary p53 inhibitor having a formula:                    
       wherein X is S, 
       m is 0 or 1,  
       n is 1 to 4,  
       R 1  and R 2  are taken together to form an aliphatic or aromatic carbocyclic 5- to 8-membered ring, and  
       R 3  is selected from the group consisting of phenyl, 4-chlorophenyl, 4-nitrophenyl, 3-nitrophenyl, 4-methylphenyl, 4-phenylphenyl, and 4-bromophenyl;  
       or pharmaceutically acceptable salts and or hydrates thereof.  
     
     
       6. A method of reducing or eliminating damage to normal tissue attributable to a treatment for a cancer comprising administering a therapeutically effective amount of a temporary p53 inhibitor to a mammal suffering from the cancer to reversibly inhibit p53 activity in a tissue sensitive to the p53 inhibitor, 
       said temporary p53 inhibitor having a formula:                    
       wherein X is S, 
       m is 0 or 1,  
       n is 1 to 4,  
       R 1  and R 2  are taken together to form an aliphatic or aromatic carbocyclic 5- to 8-membered ring, and  
       R 3  is selected from the group consisting of phenyl, 4-chlorophenyl, 4-nitrophenyl, 3-nitrophenyl, 4-methylphenyl, 4-phenylphenyl, and 4-bromophenyl;  
       or pharmaceutically acceptable salts or hydrates thereof.  
     
     
       7. A method of preventing cell death attributable to a stress-inducing cancer treatment that affects cells, said method comprising treating a cell in need thereof sensitive to temporary p53 inhibition with a therapeutically effective amount of a temporary p53 inhibitor to reversibly inhibit p53 activity, 
       said temporary p53 inhibitor having a formula:                    
       wherein X is S, 
       m is 0 or 1,  
       n is 1 to 4,  
       R 1  and R 2  are taken together to form an aliphatic or aromatic carbocyclic 5- to 8-membered ring, and  
       R 3  is selected from the group consisting of phenyl, 4-chlorophenyl, 4-nitrophenyl, 3-nitrophenyl, 4-methylphenyl, 4-phenylphenyl, and 4-bromophenyl;  
       or pharmaceutically acceptable salts or hydrates thereof.  
     
     
       8. The method of  claim 7  wherein p53 activity is inhibited for a sufficient time for the cell to recover from the stress-inducing cancer treatment.